The goal of this project is to elucidate the role of presynaptic NMDA receptor (preNMDAR) function in the hippocampus, a key brain structure involved in learning and memory. NMDA receptor activity is crucial for neuronal communication and normal brain function. Consequently, NMDA receptor dysfunction is implicated in several neurological disorders such as epilepsy, schizophrenia, autism, and Alzheimer's disease. This proposal incorporates training in a number of advanced laboratory skills in the fields of electrophysiology, molecular biology, and state of the art neuroimaging in order to conduct a detailed investigation of preNMDAR function in the hippocampus. To study the molecular and functional properties of preNMDARs we will use in vivo combinatory molecular knockdown-optogenetic strategies in addition to complimentary whole-cell patch clamp recordings using selective pharmacology and calcium imaging. In doing so, we will also examine the contribution of preNMDARs to hippocampal synaptic transmission and plasticity. Lastly, we will evaluate the ability of molecular signaling kinases and neuromodulators to regulate preNMDAR function during certain conditions of neural activity. In determining the role of preNMDAR function in the hippocampus our work will reveal novel cellular and molecular mechanisms that support learning and memory. In addition, we may contribute significant insights of synaptic mechanisms that could underlie NMDAR-associated brain deficits.